The overall direction of the Molecular Mechanisms of Tumor Promotion Section is to understand the mechanisms underlying the initial events in tumor promotion. Particular emphasis is being directed to the factors responsible for heterogeneity in the patterns of response. Protein kinase C is the receptor for the phorbol esters, the best studied class of tumor promoters in the mouse skin model. The mechanisms of protein kinase C activators which fail to induce phorbol ester-like responses are being characterized at the cellular and whole animal levels. The patterns of response are being correlated with the selectivity of the agents for cloned protein kinase C isozymes. One class of compounds which is receiving particular attention is that of the short chain monoesters of 12-deoxyphorbol, exemplified by prostratin. Although prostratin is a weak protein kinase C activator, chronic treatment of mouse skin with prostratin blocks the inflammatory and hyperplastic response of skin to subsequent treatment with the strong tumor promoter phorbol 12-myristate 13-acetate. These properties predict that prostra- tin will function as an anti-promoter. Ingenol is being examined because it possesses all elements of the phorbol ester pharmacophore except for the presence of a hydrophobic domain. We find that ingenol still retains weak activity as a protein kinase C agonist. Although all tumor promoting phorbol esters are inflammatory, the converse is not true. We have found that resiniferatoxin, an ultra-inflammatory phorbol ester, acts through a distinct mechanism, stimulating unique receptors on sensory neurons involved in pain and neurogenic inflammation. We are continuing to characterize these receptors, developing strategies to clone them and screening for the existence of endogenous analogs which may act as the normal physiological mediators of this pathway.